The candidate has four career goals, first to extend our clinical studies to physicochemical signaling in subchondral bone in OA; second to train clinician-scientists in clinical research methods and evidence-based medicine; third to establish an academic clinician-scientist track in the orthopaedic residency including an MPH degree; and fourth, mentoring junior faculty to achieve independent funding. We have recently developed new resources in the form of the Brown/VA Center for Restorative and Regnerative Medicine and an NIH COBRE grant, including senior mentorees in both, that will enhance our ability to transition individuals to independent investigator status. The research plan focuses understanding the role of subchondral bone in OA. Interest in the relationships between bone and cartilage in the initiation and/or progression of OA has been stimulated recently by observations that (1.) bone marrow edema is related to pain in OA, (2.) the progression of cartilage lesions is greater in joints with significant bone marrow edema, (3.) osteoblasts in OA undergo metabolic changes and secrete cytokines which stimulate both bone remodeling and cartilage degradation, (4.) focal AVN occurs in OA, suggesting common mechanisms, and (5.) intraosseous hypertension and hypoxia occur in OA. It is well established that osteoblasts are highly responsive to changes in their physicochemical environment and alter their cytokine expression profile in response to pressure, fluid flow, and hypoxia. Our preliminary observations indicate that changes in perfusion occur in both early experimental and human OA and bear a temporal and spatial relationship to cartilage lesions. It is clear also that osteoblasts in OA change their cytokine expression profile in ways that may be associated with increased bone remodeling and cartilage degradation. The long-term goal of these studies is to understand the role of the osteoblast and subchondral bone in OA, particularly in cartilage degradation. The hypothesis of these studies is that perturbations in perfusion, pressure and pO2 that occur in OA subchondral bone bear a functional relationship to bone remodeling and cartilage degradation and are part of a physicochemical signaling mechanism regulating osteoblast expression. Renewal of funding for the second period should yield disproportionate dividends, since we have a knowledgeable, committed mentor, solid infrastructure, interesting research questions, translational capability, strong collaborations, and have developed a plan to introduce evidence-based orthopaedics and develop a cadre of clinician-scientists interested in patient-oriented research. We have added major new program initiatives and individuals that enhance our ability to produce independent investigators. [unreadable] [unreadable] [unreadable] [unreadable]